Burden of Bowel Urgency in Patients With Ulcerative Colitis and Crohn’s Disease: A Real-World Global Study

Abstract Background Bowel urgency is a highly disruptive and bothersome symptom experienced by patients with inflammatory bowel diseases (IBD), (ulcerative colitis [UC], and Crohn’s disease [CD]). However, the burden of bowel urgency among patients with varying experiences in targeted treatment has not been consistently assessed. This real-world study explored the clinical and health-related quality of life burden of bowel urgency among patients with IBD with differing treatment experiences. Methods This cross-sectional survey included gastroenterologists and their patients with IBD across France, Germany, Italy, Spain, the United Kingdom, and the United States treated for over 3 months. Physicians provided patient demographics, clinical characteristics, and treatment history. Patients reported their health-related quality of life and work productivity. Patients with UC and CD were analyzed separately and stratified into 3 groups: Targeted therapy naïve, those receiving their first-line targeted therapy, and targeted therapy experienced. Results This study found that 17%-26% of UC and 13%-17% of CD patients experienced persistent bowel urgency, irrespective of receiving conventional or targeted therapy. Moreover, patients with bowel urgency experienced an increased clinical and health-related quality of life burden compared to patients without bowel urgency, which physicians most commonly regarded as one of the most difficult symptoms to treat, with the burden remaining substantial irrespective of their treatment experience. Conclusions Despite several current treatment options, new therapeutic strategies are necessary to provide relief from bowel urgency, one of the most challenging symptoms for people living with IBD.


Introduction
2][3] Common symptoms of IBD include chronic diarrhea, abdominal pain, gastrointestinal bleeding, weight loss, and malnutrition. 4The symptoms of abnormal anorectal function, such as bowel urgency, tenesmus, and fecal incontinence (also referred to as urge or bowel incontinence, defined as the inability to control bowel movements), 5,6 are also prevalent in patients with IBD, regardless of the presence or absence of perianal disease.
][10][11][12] Bowel urgency and fear of fecal incontinence have been reported to be the main symptoms leading to patients with UC declining participation

Study Design
Data were extracted from the Adelphi Inflammatory Bowel Disease (IBD) Disease Specific Program (DSP)™, a crosssectional survey of gastroenterologists and their consulting patients presenting in a real-world clinical setting, conducted between January 2020-March 2021 in France, Germany, Italy, Spain, the United Kingdom, and the United States.DSPs are large, multinational, observational studies collecting information on real-world clinical practice, designed to identify current disease management and patient-and physicianreported disease impact. 26][28] A geographically representative sample of physicians (n = 346) were recruited to participate in the DSP by local fieldwork agencies following the completion of a short screening questionnaire, with physicians eligible to participate provided they were personally responsible for treatment decisions and management for a minimum of 5 patients with UC and 5 patients with CD in a typical month.The data collection setting was secondary gastroenterology services (public or private hospitals, clinics, or offices).Physician participation was financially incentivized, with reimbursement upon survey completion according to fair market research rates.
Physicians were instructed to complete a patient record form for their next 5-7 consecutively consulting patients with UC or 5-8 with CD under routine care.Patients were eligible for inclusion if aged ≥18 years, with a physician-confirmed diagnosis of UC or CD and were not involved in clinical trials.Given this study assessed the clinical and HRQoL burden of bowel urgency among patients with differing levels of TT experience, UC patients were excluded from the study if they had only ever had a history of mild disease (had never received a steroid, immunomodulator or biologic, and had never had a Mayo score >4).We applied no such further inclusion/exclusion criteria in patients with CD due to the progressive nature of the disease.Furthermore, existing data pertaining to the burden of bowel urgency and its presentation by TT experience in patients with CD is lacking, and hence there is a need to generate such real-world evidence for patients with CD, regardless of disease presentation.
This physician-reported patient record form contained detailed questions on patients' demographics, clinical assessments, clinical outcomes, and treatment history.To assess bowel urgency, physicians were asked to select the symptoms relevant to the question "Which of the following symptoms is the patient currently experiencing?".Bowel urgency was evaluated by physicians checking the boxes for "Bowel movement urgency" and/or "Night-time bowel movement urgency."Physicians reported their assessment of patients' disease severity (mild, moderate, or severe) based on their own clinical judgment.Remission status was based on a Mayo score <3 for patients with UC, calculated through collection of the Mayo score stool frequency, rectal bleeding, Physician Global Assessment, and endoscopic subscore components (based on the most recent endoscopic observation), 29 and a Crohn's Disease Activity Index (CDAI) score <150 for patients with CD. 30 Completion of the physicianreported patient record form was undertaken through consultation of existing patient clinical records, as well as the judgment and diagnostic skills of the respondent physician, which is consistent with decisions made in routine clinical practice.
Each patient for whom the physician completed a patient record form was then invited to voluntarily complete a self-reported questionnaire and, upon agreement, provided their informed consent to participate.The questionnaire included validated instruments relating to the impact of the patient's condition on their HRQoL, including the EuroQol Visual Analogue Scale (EQ VAS), 31 the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), 32 and the Work Productivity and Activity Impairment (WPAI) questionnaire. 33atient-reported questionnaire forms were completed by the patient independently from their physician and returned in a sealed envelope ensuring their responses were kept confidential.Patients were not compensated for participation.

Data Analysis
Patients were stratified into those who were currently receiving conventional therapy with a duration >3 months and had never received TT (TT-naïve), patients who were currently receiving their first TT with a duration >3 months (1L-TT), and patients currently receiving their second or later TT with duration >3 months (TT-exp), in order to understand whether the burden of bowel urgency differs based on treatment experience.Patients were further stratified by the presence or absence of bowel urgency (day or night-time) at the time of data collection, in order to identify the burden of bowel urgency among patients within specific treatment groups.Data from patients with UC and CD were presented separately, given these are 2 distinct entities of IBD with differing symptomatic burdens and treatment considerations.
As the primary objective of the survey was descriptive (ie, no a priori hypotheses specified), the sample size was fixed by the duration of the survey period.Therefore, formal sample size calculations were not applicable and were not performed.Continuous data were expressed as means and SD and compared using a t-test, while categorical variables, summarized by frequencies and proportions, were compared using Fisher's exact, Mann-Whitney, or χ 2 tests, as appropriate.Missing data were not imputed, such that the base of patients for analysis could vary from variable to variable.Analyses were conducted in Stata Statistical Software 17. 34

Ethical Considerations
Using a checkbox, patients provided informed consent to take part in the survey.Data were collected in such a way that patients and physicians could not be identified directly.Physician and patient data were pseudo-anonymized.A code was assigned when data were collected.Upon receipt by Adelphi Real World, data were pseudo-anonymized again to mitigate against tracing them back to the individual.Data were aggregated before being shared with the subscriber and/or for publication.
This research was submitted to the Western Institutional Review Board, study protocol number 1-1238963-1.Data collection were undertaken in line with European Pharmaceutical Marketing Research Association guidelines 35 and as such it did not require ethics committee approval.Each survey was performed in full accordance with relevant legislation at the time of data collection, including the US Health Insurance Portability and Accountability Act 1996, 36  ).Patients were stratified into 3 treatment groups and further categorized into patients with reported bowel urgency and those with no bowel urgency.Despite receiving treatment for more than 3 months, physicians reported that 23%, 17%, and 26% of TT-naïve, 1L-TT, and TT-exp patients, respectively, were experiencing bowel urgency as a current symptom (Table 1).

Comparison of Patients With and Without Bowel Urgency
Minimal differences were observed in patient demographics and disease characteristics when comparing patients with and without bowel urgency across the treatment groups (Table 1).Among TT-naïve patients, those with bowel urgency were younger (mean [SD] 37.8 [13.9] vs 40.9 [14.6],P = .03)and had lower mean body mass index (BMI) compared to patients without bowel urgency (23.2 [3.0] vs 24.2 [3.4], P < .01).A significant difference in employment status was observed within the TT-naïve group, with 50% and 65% of patients with and without bowel urgency working full-time, respectively (P < .01).Very few differences were observed in the 1L-TT and TT-exp groups, with no significant difference in disease duration for patients with and without bowel urgency across all 3 treatment groups.

Crohn's Disease
bowel urgency and those with no bowel urgency.Physicians reported that 17%, 13%, and 15% of TT-naïve, 1L-TT, and TT-experienced patients, respectively, were experiencing bowel urgency at the time of data collection (Table 5).

Comparison of Patients With and Without Bowel Urgency
The demographic characteristics of the groups were similar irrespective of their bowel urgency status (Table 4).

Comparison of Treatment Groups in Patients With Bowel Urgency
When comparing patients with bowel urgency across the 3 treatment groups, there was a significant difference in mean age (37.5).No significant differences were observed between the groups for patient sex, BMI, or smoking status.

Discussion
This study, conducted in 5 major European countries and the United States, aimed to assess the impact of bowel urgency in patients with moderate to severe UC and patients with CD (any severity).We found that, despite being treated for their UC or CD, a substantial proportion of patients continued to experience bowel urgency, irrespective of receiving conventional or TT.For many years, UC and CD have been treated mainly with 5-ASAs, corticosteroids, and immunosuppressants.The recent development of biologics with novel mechanisms of action and small-molecule drugs has improved the treatment and thus the prognosis of IBD patients. 38However, the efficacy of currently available treatments in resolving inflammation is limited in that some patients may have an inadequate response, lose response over time, or may not tolerate a given drug, thus resulting in discontinuation of therapy or suboptimal treatment.As such, a significant unmet need remains as suboptimal treatment is associated with higher rates of surgery, hospitalization, and/or prolonged corticosteroid use as well as impaired HRQoL. 39Questionnaire; TT-naïve, patients who were currently receiving conventional therapy with a duration >3 months and had never received targeted therapy; 1L-TT, patients who were currently receiving their first targeted therapy with a duration >3 months; TT-exp, patients who were currently receiving their second or later targeted therapy with duration >3 months; WPAI, work productivity and activity impairment.
Our study found that, despite receiving treatment for their UC or CD for more than 3 months, 17%-26% of UC and 13%-17% of CD patients, depending on their experience with TT, experienced persistent bowel urgency, with physicians most commonly reporting bowel urgency as one of the most difficult to treat symptoms among this subset of patients.Overall, patients with bowel urgency were less likely to be in remission and more likely to have moderately or severely active UC or CD, were more likely to be flaring, and more likely to be receiving steroids than those without bowel urgency.Patients with bowel urgency also reported worse HRQoL and greater levels of overall work impairment than those without.These findings were largely consistent, irrespective of the patient's treatment group.
A substantial clinical and HRQoL burden remained, irrespective of treatment experience, when comparing patients with bowel urgency.However, an increased burden of disease was demonstrated among the TT-exp group, where a higher proportion of UC and CD patients were currently flaring, and among CD patients, there was a lower proportion of patients in remission and a higher proportion of moderate to severe patients.While the increased clinical burden among the TT-exp group is largely unsurprising, since these patients are likely to have received multiple treatment regimens due to their lack of response, this finding highlights the unmet need among these difficult-to-treat patients.
Despite some differences across the treatment groups, the rate of remission, as measured by the total Mayo score and CDAI, among patients experiencing bowel urgency was relatively high overall (20%-30% UC, 60%-85% CD).In the development of validated patient-reported outcomes tools for UC and CD patients, bowel urgency was found to be a relevant symptom to measure response to treatment in both UC and CD. 40In another recent study, bowel urgency was found to be 1 of the 4 key symptoms, on top of the conventional patient-reported outcomes, that may be helpful in predicting endoscopic mucosal healing status in UC. 41 Since the present study has demonstrated that patients with bowel urgency experience a substantial clinical and HRQoL burden, this suggests the need for further consideration around how remission in UC and CD is defined and highlights the relevance of tools which consider major burdensome symptoms such as bowel urgency, as a more comprehensive measure of disease activity.
While this study identified that physicians perceive bowel urgency as being one of the most difficult symptoms to resolve among this subset of patients, due to the fact that completion of the patient self-reported questionnaire was voluntary we did not investigate the patient perspective of this symptom as data were not available for all patients.Bowel urgency is commonly underreported by physicians, due to both lack of awareness and the absence of validated instruments to quantify severity and effect, therefore this study may underreport the burden of bowel urgency.A survey of patients with IBD that used choice-based conjoint analysis to estimate the relative importance of 4 common symptoms found that bowel urgency was the most important symptom to patients, followed by abdominal pain and blood in stools.Bowel urgency associated with incontinence received particularly high scores and was perceived to be more than 3 times as important as bowel urgency without incontinence. 11Hence, not only is bowel urgency viewed as a symptom that is highly difficult to resolve by physicians, but it is also regarded by patients as one of the key symptoms to be addressed.
Recent evidence-and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD have now identified the most relevant long-term achievable treatment targets to be clinical remission, endoscopic healing, restoration of HRQoL, and absence of disability.Symptomatic relief has been determined as an immediate goal since this is rated highest by patients in studies. 42ence, there exists a significant unmet need for the development of new therapeutic options to address key burdensome symptoms, such as bowel urgency, among patients with IBD.Abbreviations: FE, Fisher's exact test; TT-naïve, patients who were currently receiving conventional therapy with a duration >3 months and had never received targeted therapy; 1L-TT, patients who were currently receiving their first targeted therapy with a duration >3 months; TT-exp, patients who were currently receiving their second or later targeted therapy with duration >3 months.
Burden of Bowel Urgency in Patients With UC and CD

Limitations
This was a non-interventional study, with physicians completing forms on consecutive consulting patients with IBD to mitigate selection bias.Eligible patients were screened and selected by physicians, and it is therefore recognized that patients who were visiting physicians more often are more likely to have been included in the study.
It should be noted that the survey was designed to facilitate understanding of real-world clinical practice, and thus physicians could only report on data they had to hand at the time of the consultation.Therefore, this represents the evidence they had when making any clinical treatment and other management decisions at that consultation.These patients were encouraged, but not mandated, to complete all forms such that base sizes fluctuate across different variables.It is also acknowledged that the study relies on the accuracy of physicians when completing each record form and the willingness of patients to complete their questionnaires.To minimize the risk of collecting inaccurate data, the questionnaires were relatively short and user-friendly with electronic routing and logic applied to ensure no contradictions in responses.In addition, forms and questionnaires were completed at the time of consultation to reduce recall bias.
Finally, the cross-sectional design of this study prevents any conclusions about causal relationships, although identification of significant associations is possible.This study, nevertheless, involved a high number of physicians, working in different settings, across different geographical regions, thereby ensuring that the sample is likely to be representative of the overall population of physicians and their consulting patients with IBD.

Conclusion
This real-world study found that a substantial proportion of patients with moderate to severe UC and patients with CD experience bowel urgency, irrespective of receiving either conventional or TT.Moreover, patients with bowel urgency experience an increased clinical and HRQoL burden compared to patients without bowel urgency, with the burden remaining substantial across patients with differing levels of TT experience.Despite current treatment options, new therapeutic strategies are needed to address the most challenging symptoms in people living with IBD.

Table 1 .
Demographic and disease characteristics of patients with ulcerative colitis by bowel urgency status and treatment experience.

Table 2 .
Physician-reported patient characteristics and patient-reported outcomes in patients with ulcerative colitis and bowel urgency by treatment experience.

Table 3 .
Symptoms most commonly reported by physicians as difficult to resolve in patients with ulcerative colitis and bowel urgency by treatment experience.

Table 4 .
Demographic and disease characteristics of patients with Crohn's disease by bowel urgency status and treatment experience.

Table 5 .
Physician-reported patient characteristics and patient-reported outcomes in patients with Crohn's disease and bowel urgency by treatment experience.

Table 6 .
Symptoms most commonly reported by physicians as difficult to resolve in patients with Crohn's disease and bowel urgency by treatment experience.